title: Glutaminyl cyclase-mediated toxicity of pyroglutamate-beta amyloid induces striatal neurodegeneration.
abstract: BACKGROUND
  Posttranslational modifications of beta amyloid (Aβ) have been shown to affect its biophysical and neurophysiological properties. One of these modifications is N-terminal pyroglutamate (pE) formation. Enzymatic glutaminyl cyclase (QC) activity catalyzes cyclization of truncated Aβ(3-x), generating pE3-Aβ. Compared to unmodified Aβ, pE3-Aβ is more hydrophobic and neurotoxic. In addition, it accelerates aggregation of other Aβ species. To directly investigate pE3-Aβ formation and toxicity in vivo, transgenic (tg) ETNA (E at the truncated N-terminus of Aβ) mice expressing truncated human Aβ(3-42) were generated and comprehensively characterized. To further investigate the role of QC in pE3-Aβ formation in vivo, ETNA mice were intercrossed with tg mice overexpressing human QC (hQC) to generate double tg ETNA-hQC mice.
  
  
  RESULTS
  Expression of truncated Aβ(3-42) was detected mainly in the lateral striatum of ETNA mice, leading to progressive accumulation of pE3-Aβ. This ultimately resulted in astrocytosis, loss of DARPP-32 immunoreactivity, and neuronal loss at the sites of pE3-Aβ formation. Neuropathology in ETNA mice was associated with behavioral alterations. In particular, hyperactivity and impaired acoustic sensorimotor gating were detected. Double tg ETNA-hQC mice showed similar Aβ levels and expression sites, while pE3-Aβ were significantly increased, entailing increased astrocytosis and neuronal loss.
  
  
  CONCLUSIONS
  ETNA and ETNA-hQC mice represent novel mouse models for QC-mediated toxicity of truncated and pE-modified Aβ. Due to their significant striatal neurodegeneration these mice can also be used for analysis of striatal regulation of basal locomotor activity and sensorimotor gating, and possibly for DARPP-32-dependent neurophysiology and neuropathology. The spatio-temporal correlation of pE3-Aβ and neuropathology strongly argues for an important role of this Aβ species in neurodegenerative processes in these models.
authors.affiliation: Department of Experimental Therapy, Friedrich-Alexander-University Erlangen-Nürnberg, Palmsanlage 5, 91054 Erlangen, Germany. hans-ulrich.demuth@probiodrug.de.
authors.forename: Andreas
authors.initials: A
authors.lastname: Becker
authors.forename: Stephanie
authors.initials: S
authors.lastname: Kohlmann
authors.forename: Anca
authors.initials: A
authors.lastname: Alexandru
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Jagla
authors.forename: Fabio
authors.initials: F
authors.lastname: Canneva
authors.forename: Christoph
authors.initials: C
authors.lastname: Bäuscher
authors.forename: Holger
authors.initials: H
authors.lastname: Cynis
authors.forename: Reinhard
authors.initials: R
authors.lastname: Sedlmeier
authors.forename: Sigrid
authors.initials: S
authors.lastname: Graubner
authors.forename: Stephan
authors.initials: S
authors.lastname: Schilling
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Demuth
authors.forename: Stephan
authors.initials: S
authors.lastname: von Hörsten
mesh_terms: D019881:Aminoacyltransferases / Q000378:metabolism*; D016229:Amyloid beta-Peptides / Q000737:chemistry / Q000378:metabolism* / Q000633:toxicity*; D000818:Animals; D001522:Behavior, Animal; D003342:Corpus Striatum / Q000201:enzymology* / Q000473:pathology*; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008822:Mice, Transgenic; D009410:Nerve Degeneration / Q000201:enzymology* / Q000473:pathology; D011499:Protein Processing, Post-Translational
chemical_list: D016229:Amyloid beta-Peptides; D019881:Aminoacyltransferases; C059280:glutaminyl-peptide cyclotransferase